1. Field of the Invention
The present invention relates to new environments in which to conduct certain classes of chemical reactions. The present invention particularly relates to new methods and environments for the synthesis of useful pharmaceutical compounds such as aryloxy phenyl propylamines (e.g. Prozac; Trade Mark of Eli Lilly, Inc.), 2-aryl ethylamines (eg ephedrine) and propionic acid derivatives (eg. ibuprofen).
2. Background Art
Due to the complex molecular structure of many organic compounds which have pharmacological activity, it is common for pharmaceutically-useful agents to include one or more chiral centres. The complex structure of such compounds means that their synthesis involves many steps, and consequently where chiral centres are present, the compounds are usually prepared in the form of racemic mixtures.
The pharmacological activity of the compound is often mediated by the binding of the pharmacological agent to a target site. The more accurate the 3-dimensional fit between the pharmacological agent and the target site, the more potent the pharmacological activity, and the lower the likelihood of unwanted side-effects.
As a consequence of this, it is not unexpected that individual enantiomeric forms of a chiral compound show different pharmacological activity, differences in metabolic behaviour and different spectra of undesirable side-effects.
It is therefore desirable to ensure where possible that the end-products of synthesis of pharmaceutical compounds are enantiomerically pure.
Physicochemical methods for production of enantiomerically pure compounds usually involve multi-step synthesis incorporating one or more steps which are asymmetric, and laborious purification procedures. Such methods are not only tedious, but frequently provide relatively poor yields. Alternatively enantiomerically-pure starting materials can be used, together with enantioselective reaction steps; however, such pure starting materials are available only for a very limited number of desired compounds.
In recent years, efforts have been directed towards development of methods which are highly selective, provide a good rate of transformation, and enable easy, non-chromatographic separation and purification of the product. It has also been considered particularly desirable for the reactions to be carried out in non-aqueous solvents, since these are particularly convenient for large-scale reactions and purifications. In addition, where enantiomerically-pure reaction products cannot be obtained, changes in the physical environment in which the reactions are conducted can lead to improvements in the overall efficiency of the reaction system.
Some principle candidate classes of pharmaceutical compounds containing chiral centres which may be advantageously stereospecifically synthesized include aryl ethylamines such as ephedrine and the other sympathomimetic amines, aryl propylamines such as fluoxetine (Prozac) and the other serotonin selective uptake inhibitors, and propionic acid derivatives such as ibuprofen, naproxen and fenoprofen.
Ephedrine (α-[1-(methylamino)ethyl]benzene-methanol), originally isolated from plants of the genus Ephedra, occurs as the naturally occurring isomers 1-ephedrine and d-pseudoephedrine, and other pharmacologically active isomers include d-ephedrine and 1-pseudoephedrine. These compounds are adrenergic sympathomimetic agents and have antihistamine activity; 1-ephedrine is widely used as a bronchodilator, while d-pseudoephedrine is widely used as a decongestant. Compounds of these groups are present in a very wide range of prescription and over-the-counter pharmaceutical formulations.
The production of 1-phenylacetylcarbinol (PAC), a precursor of 1-ephedrine, by catalysis using whole baker's yeast cells in aqueous medium was one of the first microbial biotransformation processes to be used commercially. This reaction included the yeast-mediated reduction of a ketone intermediate to produce the chiral phenylacetylcarbinol, although today the more common synthetic route involves yeast-mediated condensation between benzaldehyde and pyruvate to form PAC.
The yeast-catalysed systems have utilised aqueous solvent systems, which have been found to be inconvenient for large-scale extraction and purification. Additional problems associated with the aqueous solvent systems are the low yields and low purity. Whilst the reaction has been improved by utilising immobilised cells, or cells which have been selected or genetically modified, this adds significantly to the cost of the process. The use of purified enzymes is normally prohibitively expensive, and again without the use of immobilised enzymes the yields tend to be low and purification difficult. In view of the difficulty of large-scale extraction and purification with the aqueous solvent systems, organic systems, supercritical fluid systems and liquefied gas systems have been investigated.
In our earlier International Application PCT/AU00/01543, we showed that yeast-mediated acyloin condensation of benzaldehyde could be achieved in supercritical or liquefied carbon dioxide or in liquefied petroleum gas. The use of supercritical fluids as the reaction medium in large scale reactions is advantageous as compared with conventional organic solvents since the purification and processing of the products is simpler. However, the use of such reagents requires specialised equipment design and control that add to expense.
There is accordingly still room for the current systems for synthesising pharmaceutical compounds to be improved upon.
It has now been surprisingly found by the present applicant that yeast mediated reduction reactions of organic compounds can be conducted in the absence of a solvent. The present applicant has established that a broad range of important pharmaceutical compounds containing chiral centres can be synthesized using a route in which a starting compound is subjected to a yeast-mediated reduction reaction to provide a product, which may be enantiomerically pure, and which can then be converted into one isomer of the target pharmaceutical compound. In cases where the product is a racemic mixture, the process provides improvements in process efficiencies, such as the simple isolation of a product without a liquid-liquid separation step.